Although protection from and resilience to Alzheimer's disease (AD) constitute a fundamental aspect to understanding AD pathophysiology, this is a relatively understudied area and the molecular basis of resilience to AD is largely unknown. This is a critical knowledge gap, as uncovering biological pathways of resilience could lead to the discovery of novel therapeutic or prophylactic drug targets in AD. It is clear that there are individuals who may be protected from developing AD pathology, despite advanced age and having highly penetrant genetic risk factors for AD, such as APOE ?4 allele. Additionally, there are people with cognitive resilience who remain free of cognitive decline despite having pathologic or biomarker changes of AD. Current therapeutic discovery efforts in AD are largely focused on uncovering the biological pathways that are perturbed in this condition, the key molecules in these pathways, and identification of therapeutic compounds to stop and/or reverse these perturbations. These efforts are based on the hypothesis that concerted perturbations of molecular networks that serve key biological functions underlie the pathophysiology of many common, complex diseases including AD. While it is critically important to discover perturbed molecular networks in AD, this is only one side of the coin. We postulate that application of network biology approaches to investigate individuals who are protected from and resilient to AD can uncover novel biological pathways that underlie resilience to AD. In addition to revealing novel resilience pathways, study of resilient individuals is also critical for the validation of perturbed disease networks, as we expect some of the susceptibility and resilience networks to overlap but have opposite direction of effect. Such validation efforts are essential for the translation of these discoveries to viable drug targets. In this proposal, we plan to study individuals who are protected from and resilient to AD by leveraging samples from autopsied and living human cohorts, to utilize existing and generate new molecular data, including RNA sequence (RNAseq) and whole genome sequence (WGS), and to apply analytic approaches to identify resilience networks. We will utilize single-nucleus RNAseq (snRNAseq) to identify cell-specific molecular changes of resilience in brain and validate these using iPSC- based models. To translate this knowledge to therapeutic targets, we will apply novel pharmacogenomics tools. Our proposal is responsive to the RFA-AG-18-029 and aims to: 1) Identify molecular targets of resilience to development and propagation of AD pathology in an autopsy cohort enriched for older controls; 2) Identify molecular targets of cognitive resilience in the presence of AD biomarkers in a longitudinally assessed older cohort enriched for clinically normal individuals with positive amyloid PET and APOE ?34 or ?44 genotypes; 3) Validate cell-specific molecular changes in iPSC-based models; 4) Decipher druggable targets of AD resilience and potential therapeutic compounds using systems-based pharmacogenomics tools. We will integrate our findings with those from AMP-AD, M2OVE-AD, ADNI and ADSP and share all generated data and tools.